A PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis

Chao Quan; Qian Du; Min Li; Ruizhen Wang; Qian Ouyang; Shu Su; Sangsang Zhu; Qiaoli Chen; Yang Sheng; Liang Chen; David G. Campbell; Carol MacKintosh; Zhongzhou Yang; Kunfu Ouyang; Hong Yu Wang; Shuai Chen

doi:10.1038/s41467-020-16116-9

A PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis

Chao Quan, Qian Du, Min Li, Ruizhen Wang, Qian Ouyang, Shu Su, Sangsang Zhu, Qiaoli Chen, Yang Sheng, Liang Chen, David G. Campbell, Carol MacKintosh, Zhongzhou Yang, Kunfu Ouyang, Hong Yu Wang (Lead / Corresponding author), Shuai Chen (Lead / Corresponding author)

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Abstract

Diabetic cardiomyopathy is a progressive disease in diabetic patients, and myocardial insulin resistance contributes to its pathogenesis through incompletely-defined mechanisms. Striated muscle preferentially expressed protein kinase (SPEG) has two kinase-domains and is a critical cardiac regulator. Here we show that SPEG is phosphorylated on Ser2461/Ser2462/Thr2463 by protein kinase B (PKB) in response to insulin. PKB-mediated phosphorylation of SPEG activates its second kinase-domain, which in turn phosphorylates sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (SERCA2a) and accelerates calcium re-uptake into the SR. Cardiac-specific deletion of PKBα/β or a high fat diet inhibits insulin-induced phosphorylation of SPEG and SERCA2a, prolongs SR re-uptake of calcium, and impairs cardiac function. Mice bearing a Speg3A mutation to prevent its phosphorylation by PKB display cardiac dysfunction. Importantly, the Speg3A mutation impairs SERCA2a phosphorylation and calcium re-uptake into the SR. Collectively, these data demonstrate that insulin resistance impairs this PKB-SPEG-SERCA2a signal axis, which contributes to the development of diabetic cardiomyopathy.

Original language	English
Article number	2186
Number of pages	14
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-020-16116-9
Publication status	Published - 4 May 2020

Keywords

Calcium signalling
Cardiomyopathies
Insulin signalling
Kinases

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-020-16116-9Licence: CC BY

Final Published VersionFinal published version, 3.72 MBLicence: CC BY

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Quan, C., Du, Q., Li, M., Wang, R., Ouyang, Q., Su, S., Zhu, S., Chen, Q., Sheng, Y., Chen, L., Campbell, D. G., MacKintosh, C., Yang, Z., Ouyang, K., Wang, H. Y., & Chen, S. (2020). A PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis. Nature Communications, 11, Article 2186. https://doi.org/10.1038/s41467-020-16116-9

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title = "A PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis",

abstract = "Diabetic cardiomyopathy is a progressive disease in diabetic patients, and myocardial insulin resistance contributes to its pathogenesis through incompletely-defined mechanisms. Striated muscle preferentially expressed protein kinase (SPEG) has two kinase-domains and is a critical cardiac regulator. Here we show that SPEG is phosphorylated on Ser2461/Ser2462/Thr2463 by protein kinase B (PKB) in response to insulin. PKB-mediated phosphorylation of SPEG activates its second kinase-domain, which in turn phosphorylates sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (SERCA2a) and accelerates calcium re-uptake into the SR. Cardiac-specific deletion of PKBα/β or a high fat diet inhibits insulin-induced phosphorylation of SPEG and SERCA2a, prolongs SR re-uptake of calcium, and impairs cardiac function. Mice bearing a Speg3A mutation to prevent its phosphorylation by PKB display cardiac dysfunction. Importantly, the Speg3A mutation impairs SERCA2a phosphorylation and calcium re-uptake into the SR. Collectively, these data demonstrate that insulin resistance impairs this PKB-SPEG-SERCA2a signal axis, which contributes to the development of diabetic cardiomyopathy.",

keywords = "Calcium signalling, Cardiomyopathies, Insulin signalling, Kinases",

author = "Chao Quan and Qian Du and Min Li and Ruizhen Wang and Qian Ouyang and Shu Su and Sangsang Zhu and Qiaoli Chen and Yang Sheng and Liang Chen and Campbell, {David G.} and Carol MacKintosh and Zhongzhou Yang and Kunfu Ouyang and Wang, {Hong Yu} and Shuai Chen",

note = "We thank members of the resource unit at Nanjing University for technical assistance. Thanks to the Ministry of Science and Technology of China (Grant Nos. 2018YFA0801102 to S.C. and 2018YFA0801104 to H.Y.W.), the National Natural Science Foundation of China (Grant Nos. 31671456 and 31971067 to H.Y.W.), and the Science and Technology Foundation of Jiangsu Province of China (Grant Nos. BK20161393 (Basic Research Program) to H.Y.W., and BK20190305 (Basic Research Program) to Q.L.C.), for financial support.",

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T1 - A PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis

AU - Quan, Chao

AU - Du, Qian

AU - Li, Min

AU - Wang, Ruizhen

AU - Ouyang, Qian

AU - Su, Shu

AU - Zhu, Sangsang

AU - Chen, Qiaoli

AU - Sheng, Yang

AU - Chen, Liang

AU - Campbell, David G.

AU - MacKintosh, Carol

AU - Yang, Zhongzhou

AU - Ouyang, Kunfu

AU - Wang, Hong Yu

AU - Chen, Shuai

N1 - We thank members of the resource unit at Nanjing University for technical assistance. Thanks to the Ministry of Science and Technology of China (Grant Nos. 2018YFA0801102 to S.C. and 2018YFA0801104 to H.Y.W.), the National Natural Science Foundation of China (Grant Nos. 31671456 and 31971067 to H.Y.W.), and the Science and Technology Foundation of Jiangsu Province of China (Grant Nos. BK20161393 (Basic Research Program) to H.Y.W., and BK20190305 (Basic Research Program) to Q.L.C.), for financial support.

PY - 2020/5/4

Y1 - 2020/5/4

N2 - Diabetic cardiomyopathy is a progressive disease in diabetic patients, and myocardial insulin resistance contributes to its pathogenesis through incompletely-defined mechanisms. Striated muscle preferentially expressed protein kinase (SPEG) has two kinase-domains and is a critical cardiac regulator. Here we show that SPEG is phosphorylated on Ser2461/Ser2462/Thr2463 by protein kinase B (PKB) in response to insulin. PKB-mediated phosphorylation of SPEG activates its second kinase-domain, which in turn phosphorylates sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (SERCA2a) and accelerates calcium re-uptake into the SR. Cardiac-specific deletion of PKBα/β or a high fat diet inhibits insulin-induced phosphorylation of SPEG and SERCA2a, prolongs SR re-uptake of calcium, and impairs cardiac function. Mice bearing a Speg3A mutation to prevent its phosphorylation by PKB display cardiac dysfunction. Importantly, the Speg3A mutation impairs SERCA2a phosphorylation and calcium re-uptake into the SR. Collectively, these data demonstrate that insulin resistance impairs this PKB-SPEG-SERCA2a signal axis, which contributes to the development of diabetic cardiomyopathy.

AB - Diabetic cardiomyopathy is a progressive disease in diabetic patients, and myocardial insulin resistance contributes to its pathogenesis through incompletely-defined mechanisms. Striated muscle preferentially expressed protein kinase (SPEG) has two kinase-domains and is a critical cardiac regulator. Here we show that SPEG is phosphorylated on Ser2461/Ser2462/Thr2463 by protein kinase B (PKB) in response to insulin. PKB-mediated phosphorylation of SPEG activates its second kinase-domain, which in turn phosphorylates sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (SERCA2a) and accelerates calcium re-uptake into the SR. Cardiac-specific deletion of PKBα/β or a high fat diet inhibits insulin-induced phosphorylation of SPEG and SERCA2a, prolongs SR re-uptake of calcium, and impairs cardiac function. Mice bearing a Speg3A mutation to prevent its phosphorylation by PKB display cardiac dysfunction. Importantly, the Speg3A mutation impairs SERCA2a phosphorylation and calcium re-uptake into the SR. Collectively, these data demonstrate that insulin resistance impairs this PKB-SPEG-SERCA2a signal axis, which contributes to the development of diabetic cardiomyopathy.

KW - Calcium signalling

KW - Cardiomyopathies

KW - Insulin signalling

KW - Kinases

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U2 - 10.1038/s41467-020-16116-9

DO - 10.1038/s41467-020-16116-9

M3 - Article

C2 - 32367034

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

M1 - 2186

ER -

A PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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